Breast Cysts and Aluminium-Based Antiperspirant Salts

Breast cysts and aluminium-based antiperspirant salts

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Darbre, P. (2019) Breast cysts and aluminium-based antiperspirant salts. Clinical Dermatology: Research and Therapy, 2 (1). 128. Available at http://centaur.reading.ac.uk/88553/

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Special Issue Article “Breast Cyst” Research Article

Breast cysts and aluminium-based antiperspirant salts

Philippa D Darbre* School of Biological Sciences, University of Reading, UK ARTICLE INFO ABSTRACT On the basis that aluminium-based antiperspirant salts are designed to block apocrine Received Date: July 17, 2019 Accepted Date: September 23, 2019 sweat ducts of the axilla, and that breast cysts result from blocked breast ducts in the Published Date: September 30, 2019 adjacent region of the body, it has been proposed that breast cysts may arise from

KEYWORDS antiperspirant use if sufficient aluminium is absorbed into breast tissues over long-term

usage. This review collates evidence that aluminium can be absorbed from dermal Aluminium application of antiperspirant salts and describes studies measuring levels of aluminium Breast cancer Breast cysts in breast tissues, including in breast cyst fluids. It is notable that breast cysts, as for Antiperspiran breast cancers, start most frequently in the upper outer quadrant of the breast, which is the region closest to the site of underarm antiperspirant application. Mechanistic Copyright: © 2019 Philippa D Darbre evidence is reviewed for a link between aluminium levels in breast tissue, cyst et al., Clinical Dermatology: Research And Therapy. This is an open access formation and development of breast cancer. If excessive use of antiperspirant is a article distributed under the Creative cause of breast cysts, then reduction or cessation of use could provide a preventative Commons Attribution License, which or even treatment strategy. Furthermore, if cyst formation from antiperspirant use is permits unrestricted use, distribution, an indicator of increased risk for breast cancer, then reduction in use of antiperspirant and reproduction in any medium, provided the original work is properly could also provide a strategy for reducing breast cancer risk. cited. INTRODUCTION

Citation for this article: Sudarshan Cystic disease of the breast is a common benign disorder of breast biology which Khokhar, Sourabh Verma, Chirakshi results from blockage of breast ducts and is classified according to the size of the Dhull. Breast cysts and aluminium- cysts formed [1]. If the cysts are small and typically visible only by microscopy, the based antiperspirant salts. Clinical Dermatology: Research And Therapy. condition is termed “microscopic cystic disease”. Due to the small size of such cysts, 2019; 2(1):128 diagnosis is usually only made when there is another lesion present and therefore the frequency and significance of microscopic cysts remain largely unknown. When the

cysts are palpable and over 3mm in diameter, the condition is termed Gross Cystic

Breast Disease (GCBD). The larger size of the cysts enables them to be clinically diagnosed and GCBD has been reported to occur in up to 7% of women living in

western countries [1]. This makes GCBD the most commonly diagnosed benign breast

disorder [1,2]. Although not life-threatening in itself, development of cysts causes anxiety, and treatment is invasive. GCBD arises from dilation and/or obstruction of ductal terminal lobular units (Figure1) which, due to retention of fluid, then swell up to

Corresponding author: form fluid-filled sacs [1,2]. Although gross cysts are known to be associated with Philippa D Darbre, retention of fluid and secretory material linked to the metabolic activity of the lining School of Biological Sciences, University epithelial cells [1,2], the molecular basis of cyst formation and the reasons why cysts of Reading, Hopkins Building, Reading, RG6 6UB, Tel: + 44 118-378-7035, arise so frequently in western women remain to be identified. Aluminium-based salts UK, are used as the active antiperspirant agent in underarm cosmetics to reduce sweating Email: [email protected] in the underarm area [3]. The main salts used are aluminium chloride, aluminium 01

Breast cysts and aluminium-based antiperspirant salts. Clinical Dermatology: Research And Therapy. 2019; 2(1):128. Clinical Dermatology: Research And Therapy chlorohydrate and aluminium zirconium chlorohydrate glycine aluminium is absorbed into breast tissues [4-6]. Since complexes [3]. Their mechanism of action is thought to involve antiperspirant salts are applied frequently to the underarm the formation of a physical plug at the top of the sweat ducts region and left on the skin, this allows for a continuous dermal which is composed of a mixture of damaged cells and exposure which could result in absorption of aluminium and precipitated aluminium salts [3]. This plug then prevents the deposition into underlying breast tissues. This might then give escape of sweat onto the skin surface which would otherwise rise to subsequent blockage of breast ducts if sufficient generate odour from bacterial action on the sweat as it lingers aluminium were absorbed or accumulated over long term on the skin. On the basis that antiperspirant formulations are usage. Aluminium complexes have been previously linked to the designed to block apocrine sweat ducts of the axilla, and that development of granulomas at the site of antiperspirant breast cysts result from blocked breast ducts in the adjacent application [7,8] and the use of aluminium-based vaccines is region of the body (Figure1), it has been hypothesised that also known to cause itching nodules locally at the site of breast cysts may arise from antiperspirant use if sufficient vaccination [9,10].

Figure 1: Structural features of the human breast showing the sites of breast cyst formation. The human breast is composed of a series of ducts and lobules which are lined with epithelial cells and are embedded in fatty stromal tissue. It is the lining epithelial cells which produce the milk which then flows down the ducts to the nipple. Breast cysts result from blocked ducts in the ductal terminal lobular units indicated in pink. Aluminium-based antiperspirant salts are used to block

sweat ducts in the underarm region (indicated in blue): if sufficient aluminium were absorbed over time, could the breast ducts not also become blocked by the same mechanism?

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Breast cysts and aluminium-based antiperspirant salts. Clinical Dermatology: Research And Therapy. 2019; 2(1):128. Clinical Dermatology: Research And Therapy

DERMAL ABSORPTION OF ALUMINIUM FOLLOWING 1.81g/cm2 for intact skin but this was increased to UNDERARM APPLICATION OF ANTIPERSPIRANT 11.5g/cm2 for stripped skin [14]. The Cosmetics Directive of In 2001, a report was published by Flarend and colleagues the European Union [15] recommends that these aluminium salts which demonstrated the principle that aluminium could be taken should not be applied “to irritated or broken skin” which up through the skin following application of antiperspirant to conflicts with these current practices of shaving prior to the human underarm [11]. In this study, an antiperspirant antiperspirant application and therefore ignores the regulatory formulation was applied which included the 26Al isotope and advice [15]. Furthermore, recent calculations by the BfR in thus allowed aluminium to be traced from application to the Germany estimate that antiperspirant use, in conjunction with human underarm into blood and urine [11]. Conclusions from prior shaving, may result in absorption of aluminium at levels this research were that aluminium uptake from a single exceeding tolerable weekly intake guidance, and accordingly application was small [11], but long-term effects of low-dose women have been advised in their report not to shave prior to uptake have yet to be studied. This is pertinent to breast tissue antiperspirant use [16]. in particular because this is the site adjacent to antiperspirant MEASUREMENT OF ALUMINIUM IN BREAST CYST FLUID application and also because breast tissue contains high levels Aluminium plays no known functional role in biological systems, of calcium phosphate which would generate a favourable but due to the activities of man [17], increasing levels of this chemical environment for aluminium deposition. In 2004, this non-essential metal are being found in biological tissues [18]. was followed by a clinical case report documenting The source of the aluminium cannot be specifically identified in physiological consequences following absorption of aluminium such measurements because the human population is now from use of underarm antiperspirant [12]. Uptake of aluminium exposed through diet, vaccines and antacids as well as through in a human subject was measured as rising to 4M in the blood antiperspirant use [6]. However, research has identified following the underarm antiperspirant use, and this was aluminium as now present in several human breast tissue associated with clinical symptoms of bone pain and fatigue structures (Figure 2) [6], and measurements have reported that [12]. The report documents clearly that the high plasma aluminium is widely present in breast tissue at levels varying aluminium levels and associated symptoms resulted from from 4 to 437 nmol/g dry weight [19]. If breast cysts result antiperspirant use because when antiperspirant use was from blockage of breast ducts through an aluminium-mediated stopped, the aluminium levels fell back to the normal range mechanism, aluminium should also be measurable in breast cyst (0.1-0.3M) and symptoms ceased [12]. fluids, and indeed, measurement has shown that aluminium is THE EFFECT OF SHAVING ON TRANSDERMAL UPTAKE OF widely present in breast cyst fluids, at levels varying from 11 to 330 g/L [20] (Figure 2). Classification of gross cysts into ALUMINIUM two types based on histology and on ion/protein/hormone Current cultural practices have led to aluminium-based concentrations in the cyst fluid has enabled aluminium levels to antiperspirant salts being applied to the underarm region often be measured separately in type 1 and type 2 cyst fluids. after shaving. Shaving is a procedure which can create Median levels of aluminium have been found to be higher in abrasions in the skin, loss of stratum corneum and damage from type 1 (150g/L) (range 80-330 g/L) than in type 2 hair removal [13]. This procedure could therefore be expected to result in increased transdermal uptake of aluminium, and in (32g/L) (range 11-39 g/L) breast cyst fluids, and both were vitro studies provide supporting evidence for this. Using a Franz higher than in blood serum (6g/L) (range 3-9g/L) [20]. The diffusion cell and a stripping procedure as a model for reasons for and consequences of the different levels of shaving, aluminium has been shown to be absorbed to a aluminium in the type 1 and type 2 cyst fluids remains to be greater extent through stripped than intact skin [14]. determined, but they might explain the different Na+ / K+ion Absorption of aluminium from a stick formulation containing concentrations reported in the two cyst types [2,21]. Type 1cyst aluminium chlorohydrate showed aluminium absorption of fluids have low Na+ / high K+ ion concentrations (Na+/K+<3),

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Breast cysts and aluminium-based antiperspirant salts. Clinical Dermatology: Research And Therapy. 2019; 2(1):128. Clinical Dermatology: Research And Therapy whilst, by contrast, type 2 cyst fluids contain high Na+ / low K+ Na+/K+-ATPase activity [22,23], differences in ion ion concentrations (Na+/K+>3) [2,21]. Since the electrolyte concentrations between the two main cyst types might be composition of the breast cyst fluid will depend on the Na+/K+- explained by the differences in aluminium levels in the cyst ATPase activity of the lining epithelial cells, and since chronic fluid. exposure to aluminium has been shown to alter cellular

Figure 2: Human breast tissue structures in which aluminium has been measured as present: references are indicated in parentheses.

DISPROPORTIONATE INCIDENCE OF CYSTS IN THE UPPER than the inner breast regions [19]. A similar disproportionate OUTER QUADRANT OF THE BREAST incidence also occurs for breast cancers in the upper outer quadrant of the breast [24,25]. Whilst national statistics are It is notable that breast cysts occur more frequently in the not collated for breast cysts, national statistics offices for upper outer quadrant compared with other regions of the England, Wales and Scotland have collected information breast [1]. An explanation of this disproportionate incidence is concerning the site of incidence of cancer in the breast since lacking other than there being more target ductal tissue in that 1979, and these data show that over half of breast cancers region [1]. However, coincidentally this is the location adjacent start in the upper outer quadrant (Figure 3) [24,25]. to the site of application of antiperspirant to the underarm. If Furthermore, a rising incidence in that specific region over this were an explanation, then it might be expected that recent decades [24,25] cannot be explained solely by more aluminium levels would be higher in that region of the breast. epithelial tissue in that region, and the hypothesis of a link Indeed, measurements of aluminium concentrations at four between increasing use of underarm antiperspirant and breast serial locations across the breast showed that the aluminium cancer has also been proposed [24,25]. content of defatted tissue was significantly higher in the outer

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Breast cysts and aluminium-based antiperspirant salts. Clinical Dermatology: Research And Therapy. 2019; 2(1):128. Clinical Dermatology: Research And Therapy

Figure 3: More than half of breast cancers originate in the upper outer quadrant of the breast. In the UK, incidence is recorded annually in the seven regions of the breast shown here and the percentage proportion of total incidence in each region is shown as published for the year of 2006 [25].

IS THERE A LINK BETWEEN BREAST CYSTS AND SUBSEQUENT IS THERE A LINK BETWEEN ALUMINIUM-BASED DEVELOPMENT OF BREAST CANCER? ANTIPERSPIRANT SALTS AND DEVELOPMENT OF BREAST Over the years, several studies have suggested that the CANCER? presence of gross cysts may be linked with a higher subsequent Many studies have now been published suggesting a potential risk of breast cancer development [1,2,21,26-28]. Notably, the link between exposure of the human breast to aluminium and highest incidence of cysts is in women of the 35-50 age group development of breast cancer. In terms of exposure scenarios, with a sharp decline after menopause [1,2] whilst 80% of some tissue measurements report higher levels of aluminium in breast cancers occur later in life in the over 50 age group [29], breast tissue of women with breast cancer. Using nipple which provides a compatible timeline for such a link. Many aspirate fluid, which is secreted by ductal and lobular epidemiological studies have concluded that there is an epithelial cells of the breast and therefore reflects the breast increased frequency of subsequent breast cancer in women microenvironment, aluminium, was measured at higher levels in who have had GCBD but not all [2]. This indicates that GCBD is samples from breast cancer patients than from women who did not a precancerous lesion in itself, but is suggestive of an not have cancer at the time of sampling [31]. The mean level of associated increased risk [30]. Since some studies have aluminium in the nipple aspirate fluids from women with breast suggested that those with type 1 cysts may be at greater risk cancer was 268.4+/-28.1 g/L but in unaffected women was [2,21,26-28,30], and it was the type 1 breast cyst fluids which 131.3+/-9.6 g/L [31]. Using breast tissue, other studies have contained the higher levels of aluminium [20], further research also reported higher levels of aluminium in malignant breast is justified to test whether tissue levels of aluminium might tissue than in adjacent unaffected tissue [32-35]. Only few provide a prognostic indicator. It might be that levels of epidemiological studies have attempted to address any link aluminium high enough in the breast tissue to block a breast between antiperspirant use and breast cancer. An early duct and cause formation of a cyst would be indicative of rising epidemiological study reported that within a population of levels of aluminium in the breast tissue in general, which if not breast cancer patients, those who used more antiperspirant checked or reversed, could eventually lead to development of were diagnosed at a younger age with breast cancer [36]. cancer. However, two other epidemiological studies failed to find any

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Breast cysts and aluminium-based antiperspirant salts. Clinical Dermatology: Research And Therapy. 2019; 2(1):128. Clinical Dermatology: Research And Therapy association between antiperspirant use and breast cancer growth at metastatic sites rather than at the primary site in the [37,38]. These early studies were impeded by the difficulty in breast [44]. finding control populations of women who had never been DISCUSSION AND CONCLUSIONS exposed to antiperspirant or who even understood the Published evidence is broadly supportive of proposed links difference between antiperspirant and deodorant. A more between the presence in breast tissue of excessive aluminium recent epidemiological study from Austria used actual tissue from antiperspirant use and both breast cyst formation and measurements of aluminium as a quantitative indication of breast cancer development. Further evidence over a longer exposure, and reported associations both between time frame has suggested an association between GCBD and antiperspirant use and aluminium levels in breast tissue and subsequent development of breast cancer. It would seem likely between aluminium tissue levels and development of breast that mechanisms would be different, with aluminium acting in cancer at young age [39]. Recent animal model studies back breast cyst formation through a physical mechanism involving up the concept that exposure of non-transformed breast obstruction of ducts, but in breast cancer through intracellular epithelial cells to aluminium salts can cause alterations to the molecular alterations leading to development of hallmarks of cells which result in transformation and subsequent growth of cancer in target epithelial cell(s). Such a basic difference in the cells into tumours in mice [40]. In vitro studies have shown mechanisms would be consistent with the lack of any direct links that exposure to aluminium can enable development of several but rather with more nebulous associated risks. Aluminium has a of the hallmarks of cancer [41,42] in breast epithelial cells long-established toxicological profile of cellular actions, and it including genomic instability, inappropriate proliferation and could be that the excessive build-up of aluminium leading to increased migration/invasion [6]. In addition, aluminium is a duct obstruction is indicative of rising tissue aluminium levels metalloestrogen [43] and exposure to excessive oestrogen is a which could lead to subsequent cancer formation if left risk factor for breast cancer [44]. With regard to DNA unchecked. However, the stochastic and multi-step requirements damage, aluminium has been shown to result in DNA damage for cancer development would also be consistent with the lack in in a micronucleus assay [45] and in Comet assays [46,47] of any direct link. In particular, the strong link between vitro in vivo , and using a zebra fish model [48], which support excessive oestrogen exposure and breast cancer development the potential for aluminium to generate genomic instability in [44] would be a complicating interacting factor. However, with cells and tissues. Aluminium chloride has been shown to induce such a high proportion of both cysts and cancers starting in the DNA double strand breaks in non-transformed MCF10A human same region of the breast (upper outer quadrant), and if mammary epithelial cells [49], and in these same cells, to aluminium build-up in the tissues is mechanistically involved, induce anchorage-independent growth in a soft agar assay then it becomes questionable as to whether the diagnosis of a [49] which is considered predictive of tumour growth in an cyst should be a relief or rather a warning sign of aluminium animal [50]. Furthermore, exposure of MCF10A cells to build-up in the region of the breast most prone to cancer aluminium chloride or aluminium chlorohydrate has been shown incidence, and this needs further research. If excessive use of to cause down regulation of both mRNA and protein for BRCA1 antiperspirant is a cause of breast cysts, then reduction or [51], which is a gene critical for DNA repair in breast cells, so cessation of use could provide a non-invasive preventative or much so that inherited defects are known to be associated with even treatment strategy. Furthermore, if excessive cyst increased breast cancer risk [52,53]. With regard to migration formation is an indicator of increased risk for breast cancer, and invasion, in vitro models have revealed that long-term then reduction in use of antiperspirant could also provide a exposure (>20 weeks) to aluminium salts can increase strategy for reducing breast cancer risk. Anecdotally, several migratory and invasive properties of human breast cancer cells women from the general public have told me of their in culture [54,55]. Such alterations are characteristic of the experiences of breast cysts which disappeared following metastatic process [56] and are especially pertinent to breast cessation of antiperspirant use. These observations need to be cancer where the major cause of mortality is from tumour followed up by controlled clinical studies. However, if breast

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Breast cysts and aluminium-based antiperspirant salts. Clinical Dermatology: Research And Therapy. 2019; 2(1):128. Clinical Dermatology: Research And Therapy cysts could be reversed simply by ceasing use of 8. Montemarano AD, Sau P, Johnson FB, James WD. (1997). antiperspirant, then this could reduce the health service burden Cutaneous granulomas caused by an aluminum-zirconium of this common benign breast condition. Furthermore, the complex: an ingredient of antiperspirants. J Am Acad implied anecdotal reversibility could be exploited to Dermatol. 37: 496-498. investigate cause and effect. Several studies have now 9. Habs H, Simon B, Thiedemann KU, Howe P. (1997). reported gynecomastia (excessive breast growth) in men Aluminium. Environ Health Criteria. 194: 1-207. following dermal exposure to cosmetic products containing 10. Bergfors E, Trollfors B, Inerot A. (2003). Unexpectedly high oestrogenic compounds and these products have been incidence of persistent itching nodules and delayed identified as causative because symptoms reversed upon hypersensitivity to aluminium in children after the use of cessation of exposure [57,58]. Such studies where reversibility adsorbed vaccines from a single manufacturer. Vaccine. of symptoms can be linked to cessation in use of a specific 22: 64-69. product are becoming important approaches to identifying 11. Flarend R, Bin T, Elmore D, Hem SL. (2001). A preliminary effects of endocrine disrupting agents [59]. Since cancer is not study of the dermal absorption of aluminium from a reversible condition, such studies need to be performed in antiperspirants using aluminium-26. Food Chem Toxicol. conditions linked to cancer, and the association between GCBD 39: 163-168. and breast cancer provides one possible opportunity. For this 12. Guillard O, Fauconneau B, Olichon D, Dedieu G, Deloncle reason, studies should now be performed to test the hypothesis R. (2004) Hyperaluminemia in a woman using an that cessation in use of aluminium-based antiperspirant salts aluminum-containing antiperspirant for 4 years. Am J Med. could prevent or reverse breast cyst formation. 117: 956-959. Conflict of interest 13. Turner GA, Moore AE, Marti VPJ, Paterson SE, James AG. The author has no conflict of interest. (2007). Impact of shaving and anti-perspirant use on the

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Breast cysts and aluminium-based antiperspirant salts. Clinical Dermatology: Research And Therapy. 2019; 2(1):128.